Effects of R-flurbiprofen and the oxygenated metabolites of endocannabinoids in inflammatory pain mice models.

Abstract

Pain is one of the cardinal signs accompanying inflammation. The prostaglandins (PGs), synthetized from arachidonic acid by cyclooxygenase (COX)-2, are major bioactive lipids implicated in inflammation and pain. However, COX-2 is also able to metabolize other lipids, including the endocannabinoids 2-arachidonoylglycerol (2-AG) and anandamide (AEA), to give glycerol ester (PG-G) and ethanolamide (PG-EA) derivatives of the PGs. Consequently, COX-2 can be considered as a hub not only controlling PG synthesis, but also PG-G and PG-EA synthesis. As they were more recently characterized, these endocannabinoid metabolites are less studied in nociception compared to PGs. Interestingly R-profens, previously considered as inactive enantiomers of nonsteroidal anti-inflammatory drugs (NSAIDs), are substrate-selective COX inhibitors. Indeed, R-flurbiprofen can selectively block PG-G and PG-EA production, without affecting PG synthesis from COX-2. Therefore, we compared the effect of R-flurbiprofen and S-flurbiprofen in models of inflammatory pain triggered by local administration of lipopolysaccharides (LPS) and carrageenan in mice. Remarkably, the effects of flurbiprofen enantiomers on mechanical hyperalgesia seem to depend on (i) the inflammatory stimuli, (ii) the route of administration, and (iii) the timing of administration. We also assessed the effect of administration of the PG-Gs, PG-EAs, and PGs on LPS-induced mechanical hyperalgesia. Our data support the interest of studying the nonhydrolytic endocannabinoid metabolism in the context of inflammatory pain.

• Authors: Baptiste Buisseret, Owein Guillemot-Legris, Youssef Ben Kouidar, Adrien Paquot, Giulio G Muccioli, Mireille Alhouayek
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 35 Issue 4 Pg. e21411 (04 2021) ISSN: 1530-6860 [Electronic] United States
• PMID: 33749884 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 Federation of American Societies for Experimental Biology.

Chemical References

• Biomarkers
• Endocannabinoids
• Lipopolysaccharides
• Flurbiprofen
• Carrageenan
• Capsaicin

Topics

• Animals
• Biomarkers (blood, metabolism)
• Capsaicin (toxicity)
• Carrageenan (toxicity)
• Endocannabinoids (chemistry, pharmacology)
• Flurbiprofen (pharmacology)
• Gene Expression Regulation (drug effects)
• Hyperalgesia
• Inflammation (chemically induced, drug therapy)
• Lipopolysaccharides
• Male
• Mice
• Pain (chemically induced, drug therapy)